Bruce S. McEwen

Stress represents a response of the body that promotes adaptation, via a process called “allostasis”. What leads to impaired health and to disease is the over-use or the dysregulation of this response system, and this is referred to as “allostatic load and overload”. Allostatic load is seen in animals in the wild as they attempt to maximize reproductive success, whereas allostatic overload is a more extreme version of allostatic load that is more closely associated with disease. The mediators of allostasis include hormones, the autonomic nervous system, neurotransmitters and the cytokines and chemokines. These systems interact in a non-linear fashion, operating as a network that is finely tuned and turned off when the stimulus is over and they are not needed. When these same mediators remain turned on or are turned on insufficiently, imbalance in the regulatory network results and produces cumulative wear and tear (allostatic overload) which can lead to disease. Atherosclerosis, arthritis, diabetes, obesity, certain types of memory loss, and depressive illness are accelerated by allostatic overload. Brain circuits are remodelled, leading to changes in behavior.

Stress is a factor in causing depression, and depression is growing as an economic, as well as a social problem worldwide according to the WHO Global Burden of Disease. Depressed mood is a natural reaction to something bad happening, such as loss of a loved one or a job (e.g. Nesse, R. M. Is depression an adaptation? Arch. Gen. Psychiat. 2000; 57:14-20.) and it is also a reversible state in many people after major life events. Depression is also a consequence of lack of control and lack of reward in many chronic situations (e.g. single parents, many types of jobs, caregiving of autistic children and dementia patients). These are treatable with appropriate interventions that involve societal, sociological and psychosocial methods and this aspect needs more discussion in light of the evidence for over-diagnosis and over-use of medications. Depression is prevalent at lower levels of income and education due in part to a sense of despair and helplessness, as well as conflict and poor environments, and it is often accompanied by pathophysiological conditions such as hypertension, obesity and diabetes. The plight of disadvantaged people is often overlooked in medically-oriented discussions that focus on middle- and upper-class depression.

When a person is not resilient, more serious interventions are needed, which should include social support, increased physical activity in many cases, and cognitive and other psychotherapies and mindfulness training, along with pharmaceutical or other treatments. In women, ovarian hormones play a role that is very much dependent on recently-characterized phenotypic differences in response to these hormones. Because brain circuits change with experience and under conditions of stress, it is likely that many of these interventions will help to restore normal circuitry.

Supported by NIH Grants MH58911 and MH41256 See McEwen, B.S. Protective and damaging effects of stress mediators. New England J. Med. 238: 171-179 (1998). McEwen, B.S. Allostasis and allostatic load: Implications for neuropsychopharmacology. Neuropsychopharmacology 22:108-124 (2000).McEwen, B.S. Protective and damaging effects of stress mediators: central role of the brain. Dialogues Clin. Neurosci. 8:367-381 (2006).